Targeting Mitochondrial Metabolism as a Key Vulnerability in Artemisinin-Resistant Plasmodium falciparum Malaria
Technical Report,01 Mar 2019,28 Feb 2020
Trustees of Columbia University in the City of New York New York United States
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Malaria is one of the highest infectious disease priorities for the US Military and the Military Infectious Disease Research Program MIDRP. Ensuring the future protection of US Military personnel from malaria caused by Plasmodium falciparum requires the development of new therapeutic strategies based on understanding existing mechanisms of antimalarial drug resistance and identifying chemical agents that can effectively eliminate these drug-resistant infections. In recent years, artemisinin ART resistance has been shown to result from mutations in the P. falciparum gene K13, which allow circulating young ring-stage parasites to survive ART action. Our findings have revealed that these K13 mutations alter multiple features of parasite mitochondria, which is the cellular engine that drives energy production, redox regulation, and synthesis of DNA precursors and heme. Using K13 mutant and wild-type parasites, we will implement biochemical assays to determine whether energy production, redox regulation, the respiratory process, and heme synthesis are essential to resistance. We will also search for vulnerabilities in the ART resistance mechanism that we can chemically exploit for future treatments. This work directly supports the mission of the Department of Defense to protect its personnel from drug-resistant malaria.
- Medicine and Medical Research